Inherited factors for prostate cancer prostate cancer risk have proven difficult to identify. The results of linkage analysis, the workhorse of gene finding methods for Mendelian disorders, have been notoriously difficult to validate. Within the past year, however, two independent studies have demonstrated that a region on 8q24 confers a strong risk of developing sporadic prostate cancer in men of African and European ancestries. 8q24 is the first bona fide genetic risk locus that is responsible for an appreciable fraction of sporadic prostate cancer cases in the general population, particularly, in African-American men. Our hypotheses are that a genetic variant within 8q24 initiates prostate cancer and impacts the clinical features of the disease. The discovery of this novel locus presents the opportunity to gain deeper insight into prostate cancer biology. Although the region has been identified, the causal allele and the gene that it influences remain to be determined. Since 8q is one of the most frequent regions of somatic amplification in prostate cancer, we will also have the opportunity to explore connections between the germline and somatic genomes. Understanding the genetic and molecular pathways driving prostate cancer can ultimately lead to improved diagnostic and therapeutic capabilities. From a clinical perspective, patients can be stratified into carriers and non-carriers of this risk allele to explore its impact on clinical variables, such as presentation and disease outcomes. Our goals are to elucidate the genetic pathogenesis and the clinical impact of the 8q24 variant allele on prostate cancer. The Specific Aims of this Project are to: Aim 1: To identify the causal germline allele through fine mapping of the 8q24 region Aim 2: To characterize inherited variation at 8q24 and somatic molecular associations at 8q24 Aim 3: To determine the effect of the germline 8q24 variant on clinical presentation and outcomes in prostate cancer patients